1. Field of the Invention
The present invention relates to a novel lyophilized composition containing cyclophosphamide and a low molecular weight amino acid as an excipient.
2. Description of Prior Art
Cyclophosamide is a nitrogen mustard for use as a antineoplastic for treatment of malignant lymphomas, multiple myeloma, chronic and acute lukemias, mycosis fungoides, neuroblastoma, adenocarcoma of the ovary, retinoblastoma and carcinoma of the breast. Cyclophosamide is commercially available as a sterile powder for parenteral use when reconstituted with sterile water for injection, as a tablet for oral use or as a lyophilizate to be reconstituted with sterile water for injection.
U.S. Pat. No. 4,537,883 to Alexander et al. (Mead Johnson & Co.) discloses various lyophilizates of cyclophosphamide. These lyophilizates are prepared by lyophilizing a solution of cyclophosphamide and one or more excipients and hydrating the product such that it contains about 4% moisture. The patent is based upon a comparative study of lyophilizate cakes and the dissolution time for lyophilizates of cyclophosphamide prepared using a number of excipients. The study concludes that the lyophilizate prepared with mannitol gives a better cake and faster dissolution time than the lyophilizates prepared with other excipients. The patent also teaches that the lyophilized cyclophosphamide-mannitol composition exhibits better thermal stability if it contains an equimolar amount of water based on cyclophosphamide. The preferred lyophilizate contains 20 parts cyclophosphamide, 1.25 to 2 parts water and 10 to 85 parts mannitol. Among the excipients evaluated in the patent were mannitol, sodium bicarbonate, lactose, polyvinyl pyrrolidone (PVP), arginine, and tartaric acid and combinations of mannitol and various organic acids including the mino acids glycine and arginine as secondary excipients. The lyophilizates illustrated in the patent prepared with the amino acids provided poor cakes which exhibited poor dissolution times.
A study of "The Stability of Cyclophosphamide in Lyophilized Cakes" by Kovalcik and Guillory, J. Parenteral Science & Technology, Vol. 42, No. 1, pp. 29-37 (1988) discloses sodium bicarbonate lyophilizates prepared using a 1:4 weight ratio of cyclophosphamide to sodium bicarbonate with a 5% water content of total weight of the lyophilizate. The sample cakes showed a 5% loss in potency when left at room temperature for 53 days and 4% loss in potency when stored at room temperature for 117 days.
Practical problems have occurred preparing a composition having a 1:4 ratio of cyclophosphamide to sodium bicarbonate in that special large vial sizes are required to obtain a lyophilizate cake. In addition, the solids of such ratios are not readily soluble and hydration time is undesirably long due to high sodium bicarbonate concentration and the amount of water necessary is greater than the sum of the mole equivalent of cyclophosphamide and the mole equivalent sodium bicarbonate.